Intraspinal microstimulation of the ventral horn has therapeutically relevant cross-modal effects on nociception.

Electrical stimulation of spinal networks below a spinal cord injury is a promising approach to restore functions compromised by inadequate and/or inappropriate neural drive. The most translationally successful examples are paradigms intended to increase neural transmission in weakened yet spared descending motor pathways and spinal motoneurons rendered dormant after being severed from their inputs by lesion. Less well understood is whether spinal stimulation is also capable of reducing neural transmission in pathways made pathologically overactive by spinal cord injury. Debilitating spasms, spasticity and neuropathic pain are all common manifestations of hyperexcitable spinal responses to sensory feedback. Whereas spasms and spasticity can often be managed pharmacologically, spinal cord injury-related neuropathic pain is notoriously medically refractory. Interestingly, however, spinal stimulation is a clinically available option for ameliorating neuropathic pain arising from aetiologies other than spinal cord injury, and the limited evidence available to date suggests that it holds considerable promise for reducing spinal cord injury-related neuropathic pain, as well. Spinal stimulation for pain amelioration has traditionally been assumed to modulate sensorimotor networks overlapping with those engaged by spinal stimulation for rehabilitation of movement impairments. Thus, we hypothesize that spinal stimulation intended to increase the ability to move voluntarily may simultaneously reduce transmission in spinal pain pathways. To test this hypothesis, we coupled a rat model of incomplete thoracic spinal cord injury, which results in moderate to severe bilateral movement impairments and spinal cord injury-related neuropathic pain, with in vivo electrophysiological measures of neural transmission in networks of spinal neurons integral to the development and persistence of the neuropathic pain state. We find that when intraspinal microstimulation is delivered to the ventral horn with the intent of enhancing voluntary movement, transmission through nociceptive specific and wide dynamic range neurons is significantly depressed in response to pain-related sensory feedback. By comparison, spinal responsiveness to non-pain-related sensory feedback is largely preserved. These results suggest that spinal stimulation paradigms could be intentionally designed to afford multi-modal therapeutic benefits, directly addressing the diverse, intersectional rehabilitation goals of people living with spinal cord injury.

Exploring the role of Yuxuebi tablet in neuropathic pain with the method of similarity research of drug pharmacological effects based on unsupervised machine learning.

Introduction: Having multiple pharmacological effects is a characteristic of Traditional Chinese Medicine (TCM). Currently, there is a lack of suitable methods to explore and discover modern diseases suitable for TCM treatment using this characteristic. Unsupervised machine learning technology is an efficient strategy to predict the pharmacological activity of drugs. This study takes Yuxuebi Tablet (YXB) as the research object. Using the unsupervised machine learning technology of drug cell functional fingerprint similarity research, the potential pharmacological effects of YXB were discovered and verified. Methods: LC-MS combined with the in vitro intestinal absorption method was used to identify components of YXB that could be absorbed by the intestinal tract of rats. Unsupervised learning hierarchical clustering was used to calculate the degree of similarity of cellular functional fingerprints between these components and 121 marketed Western drugs whose indications are diseases and symptoms that YXB is commonly used to treat. Then, based on the Library of Integrated Network-based Cellular Signatures database, pathway analysis was performed for selected Western drugs with high similarity in cellular functional fingerprints with the components of YXB to discover the potential pharmacological effects of YXB, which were validated by animal experiments. Results: We identified 40 intestinally absorbed components of YXB. Through predictive studies, we found that they have pharmacological effects very similar to non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. In addition, we found that they have very similar pharmacological effects to anti-neuropathic pain medications (such as gabapentin, duloxetine, and pethidine) and may inhibit the NF-κB signaling pathway and biological processes related to pain perception. Therefore, YXB may have an antinociceptive effect on neuropathic pain. Finally, we demonstrated that YXB significantly reduced neuropathic pain in a rat model of sciatic nerve chronic constriction injury (CCI). Transcriptome analysis further revealed that YXB regulates the expression of multiple genes involved in nerve injury repair, signal transduction, ion channels, and inflammatory response, with key regulatory targets including Sgk1, Sst, Isl1, and Shh. Conclusion: This study successfully identified and confirmed the previously unknown pharmacological activity of YXB against neuropathic pain through unsupervised learning prediction and experimental verification.

Activation of GPR55 alleviates neuropathic pain and chronic inflammation.

Neuropathic pain (NP) significantly impacts the quality of life due to its prolonged duration and lack of effective treatment. Recent findings suggest that targeting neuroinflammation is a promising approach for treating NP. G protein-coupled receptor 55 (GPR55), a member of the GPCR family, plays an important role in neuroinflammatory regulation. CID16020046, a GPR55 agonist, possesses promising anti-neuroinflammatory effects. Herein, the therapeutic effect of CID16020046 on NP was investigated in an NP rat model. The NP model was established using the unilateral sciatic nerve chronic constriction injury (CCI) assay. Both sham and CCI rats were intraperitoneally administered with 20 mg/kg CID16020046. NP was assessed using paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). First, we showed that GPR55 was downregulated in the spinal dorsal horn of CCI rats. After CCI rats were treated with CID16020046, the values of PWT and PWL were increased, indicating their effect on pain relief. The treated rats had attenuated release of inflammatory cytokines in the spinal cord, decreased spinal malondialdehyde (MDA) levels, and increased spinal glutathione peroxidase (GSH-PX) activity. Additionally, the increased levels of phosphorylated nuclear factor (NF)-κB p65 in CCI rats were significantly alleviated by CID16020046 treatment. Mechanistically, we showed that CID16020046 significantly suppressed the activation of the Janus kinase (JAK2)/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway in the spinal cord of CCI-treated rats. However, Colivelin TFA (a STAT3 agonist) abolished the effect of CID16020046 on JAK2/STAT3 activation. In conclusion, our data demonstrate that the activation of GPR55 by CID16020046 alleviates NP and neuroinflammation in CCI rats by mediating the JAK2/STAT3 pathway.

Neuropathic Pain Component in Patients with Ankylosing Spondylitis and the Relationship of Neuropathic Pain and Disease Activity Parameters: A Cross-Sectional Study.

OBJECTIVE: It is known that neuropathic pain frequently accompanies rheumatological diseases. In this study, neuropathic pain in Ankylosing Spondylitis(AS) and its relationship with disease activity were investigated. METHODS: Forty patients with AS were included. Laboratory data and disease status parameters were recorded. Neuropathic pain questionnaires were administered. Electrophysiological examination was performed on all patients. The relationship between neuropathic pain and disease activity parameters was investigated. RESULTS: According to the Pain Detect and LANSS questionnaire results, the rate of neuropathic pain was 57.5% and 42.5%. ASQoL, BASDAI, and ASDAS-ESH parameters are statistically significantly higher in the group with neuropathic pain according to the PainDetect (p:0.018, p:0.04, p:0.028). MASES, ASQoL, BASDAI, BASFI, and ASDAS-ESH parameters are statistically significantly higher in the group with neuropathic pain according to the LANSS (p:0.004, p:0.005, p: 0.001, p:0.005, p:0.02). Disease activity is higher in patients with neuropathic pain for both scales. Peripheral neuropathy is detected in nine patients. There is a positive correlation between disease activity parameters and neuropathic pain scales. A strong positive correlation was detected between ASQoL and BASDAI parameters and the Pain Detect questionnaire (r:0.533, r:0.606). CONCLUSIONS: The majority of patients with AS have a neuropathic pain. This condition is associated with high disease activity and adversely affects the patient's quality of life.

Amitriptyline nanoparticle repositioning prolongs the anti-allodynic effect of enhanced microglia targeting.

Aim: Amitriptyline (AMI) has been used to treat neuropathic pain. However, the clinical outcomes remain unsatisfactory, presumably due to a limited understanding of the underlying molecular mechanisms. Here, we investigated a drug repositioning strategy using a low-dose of AMI encapsulated in poly (D, L lactic-co-glycolic acid) (PLGA) nanoparticles (AMI NPs) for neuropathic pain, since PLGA nanoparticles are known to enhance delivery to microglia.Methods: We evaluated the anti-allodynic effects of AMI and AMI NPs on neuropathic pain by assessing behaviors and inflammatory responses in a rat model of spinal nerve ligation (SNL). While the anti-allodynic effect of AMI (30 µg) drug injection on SNL-induced neuropathic pain persisted for 12 h, AMI NPs significantly alleviated mechanical allodynia for 3 days.Results: Histological and cytokine analyses showed AMI NPs facilitated the reduction of microglial activation and pro-inflammatory mediators in the spinal dorsal horn. This study suggests that AMI NPs can provide a sustained anti-allodynic effect by enhancing the targeting of microglia and regulating the release of pro-inflammatory cytokines from activated microglia.Conclusion: Our findings suggest that the use of microglial-targeted NPs continuously releasing AMI (2 µg) as a drug repositioning strategy offers long-term anti-allodynic effects.

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Innovative Management of Opioid-Induced Hyperalgesia Using Lidocaine Infusion: A Case Report.

Prolonged opioid use carries risks, including addiction and dependence. A significant consequence of chronic opioid use is opioid-induced hyperalgesia (OIH), where patients experience heightened pain sensitivity. Managing OIH typically involves reducing opioid intake while mitigating withdrawal symptoms. This case report presents a patient with OIH treated with intravenous lidocaine and morphine. OIH presents complex pain management challenges, and lidocaine infusion has shown promise in mitigating its effects. Further research is needed to comprehensively assess the efficacy and safety of this treatment approach for patients with OIH.

The protective effects of orexin B in neuropathic pain by suppressing inflammatory response.

Chronic pain induced by pathological insults to the sensorimotor system is a typical form of neuropathic pain (NP), and the underlying mechanism is complex. Currently, there are no successful therapeutic interventions for NP. Orexin B is a neuropeptide with a wide range of biological functions. However, the pharmacological function of orexin B in chronic neuropathic pain has been less studied. Here, we aim to examine the neuroprotective effects of orexin B in chronic constriction injury (CCI)- induced NP. Firstly, we found that orexin type 2 receptor (OX2R) but not orexin type 1 receptor (OX1R) was reduced in the spinal cord (SC) of CCI-treated rats. Mechanical withdrawal threshold and thermal withdrawal latency assays display that administration of orexin B clearly ameliorated CCI-evoked neuropathic pain dose-dependently. Notably, orexin B treatment also effectively prevented microglia activation by reducing the levels of IBA1. Additionally, orexin B was also found to suppress the inflammatory response in the SC tissue by reducing the levels of IL-6, TNF-α, iNOS, and COX-2 as well as the production of NO and PGE2 in CCI-treated rats. Furthermore, orexin B administration attenuated oxidative stress (OS) by increasing the activity of SOD and the levels of GSH. Mechanically, orexin B prevented activation of JNK/NF-κB signaling in the SC of CCI-treated rats. Based on these findings, we conclude that orexin B might have a promising role in ameliorating CCI-evoked neuropathic pain through the inhibition of microglial activation and inflammatory response.

18 kDa Translocator protein (TSPO) is upregulated in rat brain after peripheral nerve injury and downregulated by diroximel fumarate.

Neuroimmune signaling is a key process underlying neuropathic pain. Clinical studies have demonstrated that 18 kDa translocator protein (TSPO), a putative marker of neuroinflammation, is upregulated in discrete brain regions of patients with chronic pain. However, no preclinical studies have investigated TSPO dynamics in the brain in the context of neuropathic pain and in response to analgesic treatments. We used positron emission tomography-computed tomography (PET-CT) and [18F]-PBR06 radioligand to measure TSPO levels in the brain across time after chronic constriction injury (CCI) of the sciatic nerve in both male and female rats. Up to 10 weeks post-CCI, TSPO expression was increased in discrete brain regions, including medial prefrontal cortex, somatosensory cortex, insular cortex, anterior cingulate cortex, motor cortex, ventral tegmental area, amygdala, midbrain, pons, medulla, and nucleus accumbens. TSPO was broadly upregulated across these regions at 4 weeks post CCI in males, and 10 weeks in females, though there were regional differences between the sexes. Using immunohistochemistry, we confirmed TSPO expression in these regions. We further demonstrated that TSPO was upregulated principally in microglia in the nucleus accumbens core, and astrocytes and endothelial cells in the nucleus accumbens shell. Finally, we tested whether TSPO upregulation was sensitive to diroximel fumarate, a drug that induces endogenous antioxidants via nuclear factor E2-related factor 2 (Nrf2). Diroximel fumarate alleviated neuropathic pain and reduced TSPO upregulation. Our findings indicate that TSPO is upregulated over the course of neuropathic pain development and is resolved by an antinociceptive intervention in animals with peripheral nerve injury.

Pregnancy ameliorates neuropathic pain through suppression of microglia and upregulation of the δ-opioid receptor in the anterior cingulate cortex in late-pregnant mice.

PURPOSE: Pregnancy-induced analgesia develops in late pregnancy, but its mechanisms are unclear. The anterior cingulate cortex (ACC) plays a key role in the pathogenesis of neuropathic pain. The authors hypothesized that pregnancy-induced analgesia ameliorates neuropathic pain by suppressing activation of microglia and the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and by upregulating opioid receptors in the ACC in late-pregnant mice. METHODS: Neuropathic pain was induced in non-pregnant (NP) or pregnant (P) C57BL/6JJmsSlc female mice by partial sciatic nerve ligation (PSNL). The nociceptive response was evaluated by mechanical allodynia and activation of microglia in the ACC was evaluated by immunohistochemistry. The expressions of phosphorylated AMPA receptors and opioid receptors in the ACC were evaluated by immunoblotting. RESULTS: In von Frey reflex tests, NP-PSNL-treated mice showed a lower 50% paw-withdrawal threshold than NP-Naïve mice on experimental day 9. No difference in 50% paw-withdrawal threshold was found among the NP-Naïve, NP-Sham, P-Sham, and P-PSNL-treated mice. The number of microglia in the ACC was significantly increased in NP-PSNL-treated mice compared to NP-Sham mice. Immunoblotting showed significantly increased expression of phosphorylated AMPA receptor subunit GluR1 at Ser831 in NP-PSNL-treated mice compared to NP-Sham mice. Immunoblotting also showed significantly increased δ-opioid receptor in the ACC in P-Sham and P-PSNL-treated mice compared to NP-Sham mice. CONCLUSION: Pregnancy-induced analgesia ameliorated neuropathic pain by suppressing activation of microglia and the expression of phosphorylated AMPA receptor subunit GluR1 at Ser831, and by upregulation of the δ-opioid receptor in the ACC in late-pregnant mice.

Dorsal root ganglion stimulation provides significant functional improvement from acute debilitating Crohn's disease: A novel use.

Crohn's disease is a chronic inflammatory bowel condition causing symptoms, notably pain, due to ongoing intestinal inflammation or complications like abscesses, strictures, and fistulas, which are common in IBD patients. Abdominal pain affects up to 60 % of IBD patients, irrespective of disease severity, prompting medical attention. Various medications like NSAIDs, antidepressants, antispasmodics, anticonvulsants, and opioids are used to manage pain, but they have limited effectiveness and potential side effects, even during remission. In this case, a 20-year-old Caucasian female college student [height 5'4″, weight 120lbs (54.4 kg)] with juvenile idiopathic arthritis and Crohn's disease experienced severe daily abdominal pain, negatively impacting her life. Despite a multimodal regimen, including gabapentin, nortriptyline, duloxetine, and acetaminophen, her pain persisted, significantly affecting her appetite, sleep, mood, activity level, and overall quality of life (QOL). To address this, dorsal root ganglion (DRG) stimulation was considered. The patient aimed for a 20 % pain reduction and improved QOL. Trial leads were placed along the T10 and T12 DRG, resulting in a 25 % pain reduction (8-6 out of 10) and substantial QOL improvement. She could eat, sleep without interruptions, walk longer distances, and be more active. The T12 lead was more effective than the T10, targeting upper abdomen stimulation. The patient and her mother were highly satisfied and opted for permanent implantation for the T11 and T12 DRG. While DRG stimulation was approved in 2016 for chronic pain, to our knowledge, this is the first reported case of its use in a patient with debilitating Crohn's disease.

Radiofrequency stimulation of the dorsal root ganglion as a diagnostic tool for radicular pain syndromes: six representative cases.

BACKGROUND: We discuss the diagnostic benefit of pulsed radiofrequency (PRF) of the dorsal root ganglion (DRG) in a case series of patients with different pathologies. We expand the diagnostic potential of DRG stimulation beyond paresthesia mapping by using DRG stimulation to help determine the role of the DRG in the patient's pain and narrow down the etiology. In some cases, DRG stimulation was also part of the treatment plan. METHODS: Six patients underwent DRG radiofrequency as a diagnostic/therapeutic step before considering implantation of a DRG neurostimulator. First, patients underwent a basic bedside neurological evaluation. Next, an electrode was placed in the epidural space through the sacral hiatus or between vertebral laminae. Then, sensory stimulation was applied at 50 Hz and gradually increased from 0.1 V until the patient reported paresthesia or until a maximum intensity of 2 V was reached. Patients were asked to describe where the stimulation was felt and outline the anatomical area the paresthesia covered. Then a motor stimulation was applied at 2 Hz until muscle twitching was reported by the patient or observed by the physician. RESULTS: The information obtained helped diagnose the type of lesion as principally preganglionic, ganglionic, or postganglionic. This information guided patient management. CONCLUSION: PRF of the DRG can provide valuable diagnostic information and is a useful step before ganglionic electrode implantation. In all cases, PRF of the DRG provided valuable diagnostic information and guided management options.

Osteomyelitis and Septic Arthritis of the Foot and Ankle: Imaging Update.

Radiography is considered the first-line screening exam for clinically suspected osteomyelitis. However, additional evaluation is generally needed. MRI is the definitive diagnostic exam with high sensitivity and specificity combined with excellent anatomic definition. Gadolinium contrast can be useful to detect areas of devitalization before surgery. Bone marrow edema on fluid-sensitive images and low signal intensity on T1-weighted images in the presence of secondary MRI findings, including ulcer, sinus tract, and cellulitis with or without abscess are typical findings of osteomyelitis. If MRI is contraindicated, three phase bone scan can be used. Early diagnosis and treatment is essential.

Schwann cells transplantation improves nerve injury and alleviates neuropathic pain in rats.

The mechanism of neuropathic pain induced by nerve injury is complex and there are no effective treatment methods. P2X4 receptor expression is closely related to the occurrence of pain. Schwann cells (SCs) play a key protective role in the repair of peripheral nerve injury and myelin sheath regeneration. However, whether SCs can affect the expression of P2X4 receptor and play a role in pathological pain is still unclear. Therefore, this study investigated the effect of SCs on whether they can down regulate the expression of P2X4 receptor to affect pain. The results showed that in the neuropathic pain induced by sciatic nerve injury model, the expression of P2X4 receptor in spinal cord tissue was significantly increased and the pain sensation of rats was increased. While SCs transplantation could down regulate the expression of P2X4 receptors in spinal cord and increase the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) of rats. These data indicate that SCs can reduce the expression of P2X4 receptors to alleviate neuropathic pain, indicating that SCs can mediate P2X4 receptor signalling as a new target for pain treatment.

Efficacy of Percutaneous Laser Disc Decompression (PLDD) Combined with an Oral Food Supplement for Lumbar Disc Herniation.

Background: In recent years, minimally invasive treatment options for lumbar disc herniation, such as percutaneous laser disc decompression (PLDD), have been introduced to avoid more invasive surgical methods. Combining these minimally invasive approaches with nutraceuticals that are effective in neuroprotection and pain management may lead to better long-term outcomes. Methods: The present study evaluated the beneficial effects of a new oral food supplement composed of acetyl-L-carnitine, α-lipoic acid, quercetin, bromelain, pantothenic acid, and vitamins C, B1, B2, B6, and B12 in patients with neuropathic pain due to herniated lumbar discs treated with PLDD. Patients were divided into two groups of 26 patients each: group A underwent PLDD alone, while group B underwent PLDD followed by a dietary supplement for two months after surgery. Preoperative VAS scores for leg pain were recorded for both groups and no significant difference was observed (8.7 for Group A and 8.6 for Group B). Results: In Group A, the mean postoperative VAS score for leg pain at a 1-month follow-up was 2.5, which remained stable at 3 months. In Group B, the mean postoperative VAS score was 2.0 at 1-month and improved to 1.6 at the 3-month follow-up. According to self-reported leg pain assessments, 66.5% of the patients using the dietary supplement reported a significantly better pain condition, and 43.5% reported a somewhat better situation. In contrast, 7.7% of the patients who underwent PLDD alone reported no changes in leg pain at the final follow-up. Conclusions: The results of our study indicate that the oral food supplement could provide a safe and effective treatment in patients with painful radiculopathy, enhancing the recovery of sensory fiber function in lumbar nerve roots after surgical lumbar disc decompression.

RNA-binding protein SYNCRIP contributes to neuropathic pain through stabilising CCR2 expression in primary sensory neurones.

BACKGROUND: Nerve injury-induced changes in gene expression in the dorsal root ganglion (DRG) contribute to the genesis of neuropathic pain. SYNCRIP, an RNA-binding protein, is critical for the stabilisation of gene expression. Whether SYNCRIP participates in nerve injury-induced alterations in DRG gene expression and nociceptive hypersensitivity is unknown. METHODS: The expression and distribution of SYNCRIP in mouse DRG after chronic constriction injury (CCI) of the unilateral sciatic nerve were assessed. Effect of microinjection of Syncrip small interfering RNA into the ipsilateral L3 and L4 DRGs on the CCI-induced upregulation of chemokine (C-C motif) receptor 2 (CCR2) and nociceptive hypersensitivity were examined. Additionally, effects of microinjection of adeno-associated virus 5 expressing full length Syncrip mRNA (AAV5-Syncrip) on basal DRG CCR2 expression and nociceptive thresholds were observed. RESULTS: SYNCRIP is expressed predominantly in DRG neurones, where it co-exists with CCR2. Levels of Syncrip mRNA and SYNCRIP protein in injured DRG increased time-dependently on days 3-14 after CCI. Blocking this increase through microinjection of Syncrip small interfering RNA into injured DRG attenuated CCI-induced upregulation of DRG CCR2 and development and maintenance of nociceptive hypersensitivities. Mimicking this increase through DRG microinjection of AAV5-Syncrip elevated CCR2 expression in microinjected DRGs, enhanced the responses to mechanical, heat, and cold stimuli, and induced ongoing pain in naive mice. Mechanistically, SYNCRIP bound to 3-UTR of Ccr2 mRNA and stabilised its expression in DRG neurones. CONCLUSIONS: SYNCRIP contributes to the induction and maintenance of neuropathic pain likely through stabilising expression of CCR2 in injured DRG. SYNCRIP may be a potential target for treating this disorder.

Non-invasive TMS attenuates neuropathic pain after spinal cord injury associated with enhancing brain functional connectivity and HPA axis activity.

Patients with spinal cord injury (SCI) often suffer from varying degrees of neuropathic pain. Non-invasive repetitive transcranial magnetic stimulation (TMS) has been shown to improve neuropathic pain, while the appropriate intervention strategies of TMS treatment and how TMS affects brain function after SCI were not entirely clear. To investigate the effects and mechanisms of TMS on neuropathic pain after SCI, high-frequency TMS on primary motor cortex (M1) of mice was performed after SCI and pain response was evaluated through an electronic Von-Frey device and cold/hot plates. Functional magnetic resonance imaging (fMRI), bulk RNA sequencing, immunofluorescence and molecular experiments were used to evaluate brain and spinal cord function changes and mechanisms. TMS significantly improved SCI induced mechanical allodynia, cold and thermal hyperalgesia with a durative effect, and TMS intervention at 1 week after SCI had pain relief advantages than at 2 weeks. TMS intervention not only affected the functional connections between the primary motor cortex and the thalamus, but also increased the close connection of multiple brain regions. Importantly, TMS treatment activated the hypothalamic pituitary adrenal (HPA) axis and increased the transcript levels of genes encode hormone proteins, accompanied with the attenuation of inflammatory microenvironment in spinal cord associated with pain relief. Totally, these results elucidate that early intervention with TMS could improve neuropathic pain after SCI associated with enhancing brain functional connectivity and HPA axis activity which should be harnessed to modulate neuropathic pain after SCI.

Retrospective Evaluation of Bipolar Peripheral Nerve Stimulation for Nociceptive and Neuropathic Pain: A Pilot Study.

Purpose: This retrospective review evaluates pain and patient-defined functional goal improvement utilizing bipolar peripheral nerve stimulation (PNS) in chronic neuropathic and nociceptive pain states. Patients and Methods: Our dataset includes 24 patients who underwent implantation of a permanent peripheral nerve stimulator from January 2018 through December 2022. A total of 29 leads were implanted amongst 24 patients, with 5 patients having leads at 2 different dermatomes. Fifteen leads were placed for primarily neuropathic pain, and 14 leads were placed for nociceptive pain. Inclusion criteria were the following: pain duration greater than 6 months, documented peri-procedural Numerical Pain Rating Scale (NPRS) and greater than 60 days follow-up post implant. Results: Data was collected and analyzed showing that 89.6% of implants at 6 months follow-up and 70% at 12 months follow-up achieved 50% or greater pain relief. A significant reduction in NPRS scores when comparing pre-procedure pain scores (Median = 7, n = 29) to 6-month follow-up data (Median = 2, n = 29), p<0.001 with a large effect size, r = 0.61. Ninety-three percent of patients reported achieving their personal functional goal. Twelve of the fourteen (86%) leads implanted for primary nociceptive pain and fourteen of the fifteen (93%) leads implanted for neuropathic pain achieved ≥50% relief at 6 months. At twelve months, seven leads in each group provided ≥50% sustained pain relief. Of the 14 patients that were on opioids, 6 discontinued, while another 2 had a reduction in oral morphine milligram equivalents (MME) at the 12-month follow-up. Conclusion: This retrospective review demonstrates the potential clinical application of PNS in both nociceptive and neuropathic pain states. Further prospective studies are warranted to validate the effectiveness of PNS in the treatment of refractory nociceptive and neuropathic pain states.

Efficacy and Safety of Pulsed Radiofrequency of Dorsal Root Ganglion in Elderly Patient Population With Acute and Subacute Zoster-Related Pain.

Background: Herpes zoster (HZ) is typically characterized by a burning, stabbing pain, hyperalgesia, and allodynia. In some patients, despite the lesions resolving, the pain persists and becomes chronic. If the pain continues for more than 6 months after the onset of the pain phase, this condition is called postherpetic neuralgia (PHN). The frequency and severity of PHN increase with advancing age. The pain in PHN can be severe, sometimes resistant to medications, significantly impacting the patients' quality of life. The elderly patient population cannot tolerate the medications due to their side effects. In this situation, interventional pain treatment should be applied in the elderly patient group who have a high risk of developing PHN compared to other age groups. Method: We included patients over 65 years of age with HZ-related pain who underwent dorsal root ganglion (DRG) pulsed radiofrequency (PRF) within the first 6 months from the onset of pain. We divided these patients into 2 groups: patients who underwent intervention within the first 1 month from the onset of pain and patients who underwent intervention between 1 and 6 months. We recorded medication doses and Numeric Rating Scale (NRS) scores before the procedure and at 1 week, 1 month, 3 months, and 6 months after the procedure. Results: After the DRG PRF treatment, NRS scores improved significantly in both groups (p < 0.05). The mean NRS score in the early DRG PRF group was significantly lower than that in the late DRG PRF group (p < 0.05). The medication doses in the early DRG PRF group were significantly lower than those in the other group (p < 0.05). Conclusions: Interventional pain treatment should be applied as soon as possible in the elderly patient group who do not respond to first-line medical treatment or cannot tolerate medical treatment due to its side effects and who have a high risk of developing PHN compared to other age groups. DRG PRF, applied in the early period of medical treatment-resistant acute HZ, is safe and effective, preventing the progression to PHN.

Dock4 contributes to neuropathic pain by regulating spinal synaptic plasticity in mice.

Introduction: Neuropathic pain (NP) conditions arising from injuries to the nervous system due to trauma, disease, or neurotoxins are chronic, severe, debilitating, and exceedingly difficult to treat. However, the mechanisms of NP are not yet clear. Here we explored the role of Dock4, an atypical Rac1 GEF, in the development of NP. Methods: Mechanical allodynia was assessed as paw withdrawal threshold by a dynamic plantar aesthesiometer. Immunofluorescence staining was conducted to investigate the expression and localization of Dock4, Rac1 and GluN2B. Quantitative analysis of Dock4, Rac1 and GluN2B were determined by qRT-PCR and Western blot assay. Spontaneous excitatory and inhibitory postsynaptic currents in spinal cord slices were examined using whole cell patch clam. Dendritic spine remodeling and synaptogenesis were detected in cultured dorsal spinal neurons. Results and discussion: We found that SNL caused markedly mechanical allodynia accompanied by increase of Dock4, GTP-Rac1and GluN2B, which was prevented by knockdown of Dock4. Electrophysiological tests showed that SNL facilitated excitatory synaptic transmission, however, this was also inhibited by Dock RNAi-LV. Moreover, knockdown of Dock4 prevented dendritic growth and synaptogenesis. Conclusion: In summary, our data indicated that Dock4 facilitated excitatory synaptic transmission by promoting the expression of GluN2B at the synaptic site and synaptogenesis, leading to the occurrence of NP.

A systematic review of steroid use in peripheral nerve pathologies and treatment.

Background: The use of corticosteroids has become a part of the standard of care in various pathologies but their use in peripheral nerve injury treatment is limited. Given corticosteroids' anti-inflammatory properties and their regulatory role in neuronal protein production and myelination, corticosteroids could serve as an adjunct therapy for peripheral nerve injuries. This review aims to systematically investigate the current use of corticosteroid treatment in peripheral nerve pathologies. Methods: The systematic search was performed on PubMed, MEDLINE, EMBASE, Scopus, Cochrane, and Web of Science using keywords such as "corticosteroid treatment," "peripheral nerve damage," "peripheral neuropathy," and "complications." The PRISMA guidelines were used to conduct the systematic review and all articles were reviewed by the corresponding author. After the initial search, individual study titles and abstracts were further screened and categorized using an inclusion and exclusion criteria followed by a final full-text review. Results: Out of the total 27,922 identified records, 203 studies were included based on the selection criteria. These studies focused on the use and efficacy of steroids across a spectrum of compression and non-compression peripheral neuropathies such as cubital tunnel syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. Various studies noted the promising role of steroids in offering pain relief, nerve block, and nerve regeneration effects. Additionally, safety considerations and potential complications regarding steroid use in peripheral nerve injuries were analyzed. Conclusion: While there is currently limited clinical utilization of corticosteroids in peripheral nerve pathologies, the anti-inflammatory and regenerative effects that steroids provide may be a beneficial tool in managing various peripheral neuropathies and their associated pain. Additional clinical trials and investigation into the mechanism of action could improve the reputation of steroid use as peripheral nerve injury treatment.